Osteoporosis affects more than 28 million people in the United States and the lifetime risk for osteoporosis- related morbidity is higher than a woman's combined risk for breast cancer, endometrial cancer and ovarian cancer. Health care expenditures for osteoporotic patients in this country are nearly 13 billion dollars per annum;therefore, identifying genetic elements that are important to bone health will improve the understanding of the etiology of osteoporosis and may lead to novel treatments to prevent and treat the disease in the future. Previously, we have performed genome-wide association meta-analyses on bone phenotypes including bone mineral density (BMD) and osteoporotic fractures in adult Caucasian subjects1 Although more than 30 loci reached genome-wide significance (5x10-8) and were replicated in Caucasian populations, causal variants involved in the pathophysiology of osteoporosis in those loci still need to be elucidated. Therefore, to identify potential causal variants, we propose to re-sequence targeted genomic regions (identified by GWAS) in 325 individuals with the lowest extremes of BMD) from the Framingham Study. This resequencing effort will be combined with a resequencing project (442 cases and 712 controls) that is currently underway in a very limited sample of Framingham subjects through a grant supporting this work in the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium. By resequencing additional subjects in the Framingham Osteoporosis Study, our total sample size of 1,379 will provide sufficient power to be able to detect low frequency and rare variants that are likely to be the ones that affect bone density phenotypes. To replicate the sequencing findings, we will then genotype associated novel variants in 2,500 additional family members of the re-sequenced individuals from the Framingham Osteoporosis Study cohort as well as 3,000 individuals (1,500 cases with the lowest and 1,500 controls with highest extremes of BMD) from an independent cohort, the Rotterdam Study. Our proposal leverages unique, existing clinical, epidemiological and genetic data from the Framingham Study, the Rotterdam Study, as well as the CHARGE and GEFOS consortia. Our proposed project is highly responsive to the scope of the PAR 09-135 in applying high- throughput next generation deep sequencing technologies to follow-up genome-wide significant associated loci from our previous GWAS(the largest GWAS meta-analysis so far for BMD). Our proposed aims have the potential to uncover more of the as-yet unaccounted heritability in osteoporosis. Identifying genetic elements that are important to bone health will improve the understanding of the etiology of osteoporosis and may lead to novel treatments to prevent and treat this disease in the future. PUBLIC HEALTH RELEVANCE: This research is relevant to public health in that it will be able to identify new genes that increase the risk for osteoporosis which may eventually lead to better identification of individuals who are at increased risk for fracture. The newly discovered genes will identify previously unsuspected disease pathways that may lead to new treatments for osteoporosis.